This invention relates to a process for preparing substituted 2-thioxopenams which are useful in the preparation of known penem antibiotics (7). The process may be conducted enantiospecifically to produce the latter in their correct enantiomeric state necessary for full antibacterial activity. ##STR5## wherein: R.sup.6 and R.sup.7 are independently selected from: hydrogen; R.sup.9 NH--(R.sup.9 is acyl or H); substituted and unsubstituted: alkyl, alkenyl, alkynyl, having 1-6 carbon atoms; aryl, such as phenyl; heterocyclyl, heteroaryl, having 1-4 heteroatoms selected from O,N,S; cycloalkyl, and cycloalkenyl; wherein said substituent or substituents are selected from: halo (chloro, bromo, fluoro, iodo), hydroxyl, cyano, carboxyl, amino, and the above-recited values for R.sup.6 /R.sup.7. R.sup.6 and R.sup.7 are described in detail below; however, it should be noted now that the term "acyl" in the foregoing definition means those acyls known to be effective in the related bicyclic .beta.-lactam antibiotic art, such as the penicillins and cephalosporins. In this regard the definition of acyl recited in U.S. Pat. No. 4,226,866 (issued 10-7-80) is incorporated herein by reference. Also, with respect to R.sup.6 and R.sup.7, it should be noted that reactive functional groups carried by R.sup.6 /R.sup.7, such as, amino, hydroxyl, or carboxyl, for example, may be covered by conventional blocking groups, such as p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and triorganosilyl, wherein the organo moiety is selected from alkyl having 1-6 carbon atoms, phenyl, and phenylalkyl.
R.sup.2, in functional terms, is a group which potentially forms a stable carbonium ion, for example: trityl; (--C(C.sub.6 H.sub.5).sub.3); PA1 bis(methoxyphenyl)methyl, ##STR6## 2-(diphenyl)isopropyl, ##STR7## 2,4-dimethoxybenzyl, ##STR8## and the like. M is a thiophilic metal such as silver, thallium, mercury, or the like. PA1 R.sup.1 is a removable protecting group such as allyl, p-nitrobenzyl, or a biologically removable group, for example: pivaloyloxymethyl, pivoloyloxyethyl, ethoxycarbonyloxymethyl, phthalidyl, or the like; in short, R.sup.1 is selected from any of the conventionally employed protecting groups, or pharmaceutically acceptable ester moieties known in the classical (penicillins, and cephalosporins) and nonclassical (e.g., carbapenems, and penems) .beta.-lactam antibiotic art (see for example, U.S. Pat. No. 4,226,866, which is incorporated herein by reference to the extent that it discloses such ester moieties). PA1 X is a leaving group such as substituted or unsubstituted: phenoxy, alkoxy, phenylthio, or alkylthio having 2 to 7 carbon atoms; halo (chloro or bromo), and the like, wherein, for example, such substituents are: chloro, nitro, methyl, and the like. PA1 R.sup.8, representatively defined below, is, inter alia, substituted and unsubstituted: alkyl, aryl, heteroaryl, heterocyclyl, and the like; wherein the substituent or substituents are selected from: amino, cyano, amidino, carbamoyl, hydroxyl, acyl, acyloxy, carboxy, and the like. PA1 CH.sub.3, --CH.sub.2 CH.sub.3, --CH.sub.2 CONH.sub.2, CH.sub.2 CN, CH.sub.2 CH.sub.2 OH, CH.sub.2 CH.sub.2 CN, CH(Me)CH.sub.2 CONH.sub.2, CH(Me)CH.sub.2 CN, CH.sub.2 (CH.sub.3)CHCN, ##STR14## CH.sub.2 COCH.sub.3, ##STR15## CH.sub.2 CO.sub.2 R, where R=Me, Et, allyl or pharmaceutically acceptable ester. PA1 R.sup.1 =CH.sub.2 CH.dbd.CH.sub.2 or p-nitrobenzyl (PNB)
The ultimate penem antibiotics 7, including the foregoing definitions for R.sup.1, R.sup.6, R.sup.7 and R.sup.8, are representatively disclosed in the following publications and pending U.S. Patent applications, all of which are incorporated herein by reference for the purpose of defining 7 and its utility as an antibiotic: U.S. Pat. No. 4,260,618 (4/7/81); U.S. Pat. No. 4,215,124 (7/29/80); U.K. Patent Application G.B. No. 2013674A (8/15/79); U.K. Patent Application G.B. No. 2042520A (9/24/80); and U.S. patent application Ser. Nos. 353,451, filed Mar. 1, 1982; 353,450, filed Mar. 1, 1982; 353,454, filed Mar. 1, 1982; 353,453, filed Mar. 1, 1982; and 373,008, filed Apr. 29, 1982.
The conversion process of appropriately substituted 2-thioxopenams 5 to the corresponding antibiotic 2-SR.sup.8 -pen-2-em-3-carboxylic acids 6 is known; as is the final deblocking step 6 to 7: ##STR9## wherein R.sup.8 X.degree. is an alkylating agent; X.degree. is bromo or iodo, for example; and R.sup.8 is as defined above, for example, cyanomethyl, cyanoethyl, or the like. R.sup.8 is additionally defined below. With respect to the formation of 5 and its conversion to 6, see U.K. Patent Application GB No. B 2074563A; or J. Chem. Soc. Chem. Cummun. No. 13, pp 713-714 (1982), which are fully incorporated herein by reference.
In the previous process referred to above (wherein R.sup.6 is hydrogen and R.sup.7 is protected hydroxyethyl) the thioxopenams are prepared by a distinctly different process where the C.sub.5 -C.sub.6 positions have the cis configuration. This is a result of two factors. First, the 3-substituted-4-alkylthioazetidinone intermediates are obtained with the C.sub.3 -C.sub.4 trans configuration and, second, the ring closure step involves displacement at the C.sub.4 carbon atom causing an inversion at this position. Thus the known alkylation of the cis-thioxopenams produces the undescribed and antibacterially inferior 5,6-cis-2-alkylthiopenems which are converted to a mixture containing the 5,6-trans-penems by a thermal equilibration. The present invention maintains the stereochemical integrity of the substituent on the intermediate azetidinone throughout the conversion to thioxopenams and alkylthiopenems. Thus it provides the preferred 5R,6S-6(1-R-hydroxyethyl)penems from the azetidinone nucleus derived from 6-aminopenicillanic acid.